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Mutations That Prevent Heart Attacks Upend The Search For New Drugs

Heart attacks and strokes kill more human beings than any other cause, claiming 14 million lives annually, according to the World Health Organization. Essentially, they are a plumbing problem: particles of cholesterol accumulate inside blood vessels, irritating them until one bursts into a violent clot that blocks the flow of blood to the heart or brain. But it’s still unclear what mix of harmful proteins, fat, and cholesterol causes these lethal explosions.

Now scientists have found a clue: patients with mutations that break a gene the body uses to make fat particles called triglycerides have a 40% reduction in their risk of heart attacks and strokes. The results, found by two independent groups and published last night in the New England Journal of Medicine, are likely to upend the thinking of many scientists when it comes to the culprits behind heart attacks and strokes, turning triglycerides from an ignored supporting character into a major villain.

Low-density lipoprotein, or LDL cholesterol, targeted by changes in diet and popular statin drugs, remains public enemy number one. But triglycerides may be the next-most important thing. And high-density lipoprotein (HDL), the so-called “good cholesterol” that is supposed to protect you from heart attacks and strokes and has been a major target of drug companies, may be less important still – it may even be just an inactive bystander.

“In medical school we were told to ignore triglycerides and focus on HDL,” says Ethan J. Weiss, an associate professor at the University of California, San Francisco, School of Medicine. “It turns out that we probably had it backwards, and that we should be paying attention to triglycerides and ignoring HDL.”

For companies testing new heart drugs, a field in which billions of dollars are at stake, the results are a game changer. A drug already in development that targets the triglyceride gene, made by Isis Pharmaceuticals of Carlsbad, Calif., is likely to suddenly become a hot property. The odds of success for big studies of fish oil pills made by Amarin Pharmaceuticals and by AstraZeneca just went up. And the prospects for expensive heart pills being tested by Merck and Eli Lilly may have changed, too.

“This is a big deal,” says Steven Nissen, chair of cardiology at the Cleveland Clinic, who is running clinical trials for Lilly and AstraZeneca. “Nobody has been absolutely sure of the role of triglycerides in heart disease. And while these kinds of studies don’t prove triglyceride-lowering heart drugs will work, they do lay the groundwork.”

A Search For Mutations

In 2009, Sekar Kathiresan, Director of Preventative Cardiology at Mass General Hospital and an Associate Member of the Broad Institute, a leading center for DNA-based research, got a grant from the National Heart Lung and Blood Institute. It was part of the stimulus package, intended to increase science funding as it tried to pull the U.S. back from a recession.

The experiment was to sequence the genes of thousands of people using high-tech machines made by San Diego’s Illumina to see if they could learn about heart disease. Kathiresan’s team looked at 3,734 people from the project for whom triglycerides and the DNA sequences of all their genes – known as an exome. Then, they looked for genetic mutations – basically, unusual spellings in the DNA that codes for genes — that appeared in people with high triglycerides.

One gene kept popping up: APOC3, a protein that binds to very small cholesterol and fat particles and is associated with high triglycerides. They found 33 people with 7 different APOC3 mutations, all of which made the gene stop working. As a result, their triglyceride levels were decreased, on average, 40%, compared to people without the mutation. (The mutation broke one copy of the gene, but people have two; the second picked up some of the slack.)

Then the researchers looked for mutations in APOC3 in 110,970 people, and found that those who one bad copy of APOC3 had a 40% reduction in their risk of heart attacks and strokes. A second group in Denmark, looking at APOC3 as a way to study triglycerides, found that having a defective copy of APOC3 resulting in a 44% decrease in triglyceride levels and a 41% reduction in the risk of heart attacks and strokes.

Because this is due to a genetic difference, the researchers can be pretty sure that this reduction is due to the importance of triglycerides, and not because triglycerides are lower when people eat better or exercise more. “It’s like nature’s randomized trial,” says Anne Tybaerg-Hansen of the University of Copenhagen, who led the Danish study.

The Danes keep better medical records than Americans, because of a well-developed electronic health records system; using those, Tybaerg-Hansen was able to show there is no relationship between having one of the triglyceride-lowering genes cancer. The American team did CAT scans to prove that the genes don’t lead to fatty liver disease, another worry.

Impact On Drug Development

For years, Big Pharma has been deeply invested in the idea that HDL would be the next big step in controlling cholesterol. The attack on LDL was launched by Merck, which proved that its Zocor prevented heart attacks and strokes back in 1995, but in the end led by Pfizer, for whom the cholesterol-lowerer Lipitor became the best-selling drug ever, with annual sales of $11 billion, before it lost patent protection in 2011.

Studies showed that patients with high HDL were less likely to have heart attacks. So Pfizer spent $1 billion on rushing a medicine to raise HDL, called torcetrapib, through clinical trials. It not only failed, it proved to be harmful, with more patients who got torcetrapib dying or getting heart attacks than those who received placebo.

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